2021 Fiscal Year Final Research Report
Identification of blood-brain barrier transporters using sgRNA library
| Project/Area Number |
20K16039
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Keywords | 血液脳関門 / 薬物トランスポーター / 脳移行性 / スクリーニング |
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| Outline of Final Research Achievements |
The present study aimed at identifying drug uptake transporter in blood-brain barrier (BBB) model hCMEC/D3 cells using a knockdown/knockout screening study targeting membrane transporters, including uncharacterized ones. The reported and estimated unbound brain to plasma concentration ratio values of 65 kinds of drugs were investigated, and 10 drugs, which exhibited higher Kp,uu,brain, were selected for following screenings. According to studies of siRNA knockdown screening in hCMEC/D3 cells, OCTN2 was identified as candidate transporter gene for aripiprazole. On the other hand, by the knockout screening with the consideration of the expression of extracted genes in human BBB, 10 genes were found as BBB uptake transporter candidates. In conclusion, knockdown and knockout screening are useful approaches for identifying BBB transporters.
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| Free Research Field |
薬物動態学
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| Academic Significance and Societal Importance of the Research Achievements |
一部のカチオン性薬物の脳移行には、血液脳関門（BBB）に発現する取り込み型輸送体の関与が示唆されている。このようなBBB取り込み輸送体の同定により中枢疾患治療薬の研究開発を効率的に進めることができると期待される。未知のBBB輸送体を同定するには対象輸送体分子を限定しないより包括的なスクリーニングが有用である。推定された輸送体のみに検討を絞った従来の限定的な手法と比べ、本手法は未知の薬物輸送体を同定する手法として有用であることが示唆された。今後、BBBの薬物輸送体を同定することで、輸送体を利用した中枢疾患治療薬の開発への応用が期待される。
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